作者: Chen, Xiu-Cai ; Tan, Jia-Heng ; Chen, Shuo-Bin ; Ou, Tian-Miao ; Wu, Tian-Ying ; Dai, Jing ; Dai, Le-Tian ; Li, Wen-Wei ; Huang, Zhi-Shu ; Tang, Gui-Xue

Mutations in NRAS promote tumorigenesis and drug resistance. As this protein is often considered an undruggable target, it is urgent to develop novel strategies to suppress NRAS for anticancer therapy. Recent reports indicated that a G-quadruplex (G4) structure formed in the untranslated region of NRAS mRNA can downregulate NRAS translation, suggesting a potential NRAS suppression strategy. Here, we developed a novel cell-based method for large-scale screening of NRAS G4 ligand using the G-quadruplex-triggered fluorogenic hybridization probe and successfully identified the clinically used agent Octenidine as a potent NRAS repressor. This compound suppressed NRAS translation, blocked the MAPK and PI3K-AKT signaling, and caused concomitant cell cycle arrest, apoptosis, and autophagy. It exhibited better antiproliferation effects over clinical antimelanoma agents and could inhibit the growth of NRAS-mutant melanoma in a xenograft mouse model. Our results suggest that Octenidine may be a prominent anti-NRAS-mutant melanoma agent and represent a new NRAS-mutant melanoma therapy option.

2019-02-01·Cell1区 · 生物学

Pharmacological Targeting of STK19 Inhibits Oncogenic NRAS-Driven Melanomagenesis

1区 · 生物学

Article

作者: Deng, Xianming ; Xu, Zhi-Xiang ; Liu, Tongzheng ; Zhang, Ting ; Wei, Guo ; Zhang, Jie ; Cui, Rutao ; Chen, Shuyang ; Huang, Canhua ; Li, Li ; Zhu, Bo ; Wang, Peng ; Wei, Zhi ; Goding, Colin R ; Miao, Xiao ; Liu, Yu ; Gao, Xiumei ; Mi, Xia ; Li, Shanshan ; Yin, Chengqian ; Li, Xin

Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation. STK19^D89N knockin leads to skin hyperpigmentation and promotes NRAS^Q61R-driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new and viable therapeutic strategy for melanomas harboring NRAS mutations.

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